DESCRIPTION: (Applicant's Abstract) Activation of tumor destructive effector cells can be accomplished by in vivo administration of cytokines such as IL-2. Enhancement of tumor selective reactivity by these cytokine-activated-effectors can be accomplished using monoclonal antibodies (mAb), that are selectively able to recognize human tumors, provided they can facilitate antibody dependent cellular cytotoxicity (ADCC). Clinical trials are now underway testing co-administration of effector-activating cytokines and tumor reactive mouse or chimeric antibodies. The applicant's team is testing the combined effects of IL-2 with the chimeric anti-GD2 antibody ch14.18 in patients with melanoma and other GD2+ tumors. However, the use of systemic IL-2 does not localize the effector cell activation process to the cellular micro-environment where tumor cells are located. In order to better localize effector cell activation to sites of tumor growth, the fusion protein (FP) ch14.18-IL-2 was created, which linked the human IL-2 molecule to the Fc end of each heavy chain of the ch14.18 mAb. This ch14.18-IL-2 FP can mediate potent ADCC with in vitro activated IL-2 responsive effectors, and mediate protective anti-tumor reactivity in SCID mice bearing micrometastases of a GD2+ human tumor. They have been testing this reagent with human cells in vitro and in vivo for murine toxicity/pharmacology studies. In this application, they plan to further clarify the immune pathways utilized by this FP to activate anti-tumor reactivity, finalize needed preclinical data required to initiate clinical testing in a Phase I trial, and evaluate the in vivo physiologic and immunologic effects of this FP in treated patients. To accomplish this they propose to: (1) measure the activity and efficacy of clinical grade FP in vitro and determine the pathways of target cell lysis, and effector cell activation utilized by this molecule. (2) Complete in vivo murine testing required to finalize IND application and initiate human trials. In vivo preclinical testing will be performed using similar regimens anticipated for use in the clinical testing, in order to model the specific variables to be studied subsequently in GD2+ tumor bearing patients. (3) Initiate and complete a four-part Phase I/IB trial of ch14.18-IL-2 in patients with GD2+ tumors. (4) Perform detailed laboratory analyses on tumor biopsies, serum, and peripheral blood leukocytes from patients participating in these clinical trials. The goal of these in vitro, preclinical and clinical studies is to determine: (a) how best to utilize mAb-cytokine FPs as a means to initiate effector cell activation at micrometastatic sites, and (b) identify a dose and regimen for subsequent Phase II testing of the ch14.18-IL-2 FP in patients with GD2+ tumors.